DEVELOPMENTAL AND HORMONAL REGULATION OF APOLIPOPROTEIN B GENE EXPRESSION

我们研究了大鼠载脂蛋白B(ApoB)的表达 并首次报道了apoB基因在体内的相关性。 编辑活性和RNA编辑蛋白(REPR)的表达。 我们证明了apoB mRNA编辑的正常发展需要 甲状腺激素(T3)，而T3调节Repr的mRNA水平。我们克隆了 人与大鼠REPRR同源物的组织特异性表达；这 推测的人类形式的REPR基因包含一个锌指结构域，具有100% 与转录因子YY-1同源。 目前的实验室研究包括：(1)确定调控要素 大鼠和人Repr基因启动子的相互作用；(2)体外检测 RepR在肝、肠和HeLa细胞系中的表达； 利用一种新的转基因和基因敲除Repr小鼠 方法学--RNA/DNA杂交法。在这个过程中，RNA以 与基因组中的特定区域杂交，DNA部分就能够 进行同源重组，插入所需的改变 基因组。该方法现在可以在培养的细胞中诱导单个碱基变化 细胞。在我们的临床研究中(1)我们检测了肠道载脂蛋白B的mRNA 对8例早发冠状动脉疾病患者队列的编辑 和15名正常志愿者，并报告了第一例缺陷 肠道基因编辑与过早动脉粥样硬化的关系；(2) 我们从一个患有脂蛋白的儿童的脂肪组织中提取了mRNA。 脂肪酶缺乏症(LPL)和几名正常患者，并合作在 LPL转录的定量；我们观察到这种情况 LPL缺乏症继发于LPL转录后缺陷 表达；(3)我们已经开始与另一个部门合作 LMTB在正常人和正常人IL-4受体表达特征中的作用 动脉粥样硬化斑块中活化的巨噬细胞(泡沫细胞)； 一项研究已经开始评估降脂药物烟酸的效果， 系统性红斑狼疮患者明显致动脉粥样硬化脂蛋白Lp(A)的研究 红斑狼疮(SLE)；(5)另一项研究正在评估甲状腺激素 诱发甲状腺癌患者Lp(A)的变化。在治疗期间 对于甲状腺癌，甲状腺激素水平是医学上的。 不同的，允许高水平和低水平的甲状腺激素对 Lp(A)待定。

We characterized apolipoprotein B (apoB) expression during rat development, and reported the first in vivo correlation between apoB mRNA editing activity and the expression of an RNA editing protein (REPR). We demonstrated that the normal development of apoB mRNA editing requires thyroid hormone (T3), and that T3 modulates REPR mRNA levels. We cloned the tissue specific expression of a human homologue to rat REPR; this putative human form of REPR gene contains a zinc-finger domain with 100% homology to the transcription factor YY-1. Current laboratory studies include: (1) defining the regulatory elements of the rat and human REPR gene promoter; (2) examining the in vitro expression of REPR in liver, intestinal and HeLa cell lines; (3) developing transgenic and knockout REPR mice using a new methodology--RNA/DNA hybrids. With this procedure the RNA targets the hybrid to a specific region in the genome, the DNA portion is then able to undergo homologous recombination inserting the desired change within the genome. The method can now induce a single base change in cultured cells. In our clinical studies (1) we examined intestinal apoB mRNA editing in a cohort of 8 patients with premature coronary artery disease and 15 normal volunteers, and reported the first example of a defective mRNA intestinal editing associated with premature atherosclerosis; (2) we isolated mRNA from the adipose tissue of a child with lipoprotein lipase deficiency (LPL) and several normal patients,and collaborated in the quantitation of LPL transcription; we have observed that this case of LPL deficiency is secondary to a post-transcriptional defect in LPL expression; (3) we have initiated a collaboration with another section of LMTB in the characterization of IL-4 receptor expression in normal vs. activated macrophages (foam cells) in the atherosclerotic plaque; (4) a study has begun evaluating the effect of niacin, a lipid lowering drug, on the markedly atherogenic lipoprotein Lp(a) in patients with systemic lupus erythematosus(SLE); (5) another study is evaluating thyroid hormone induced changes in Lp(a) in thyroid cancer patients. During treatment for thyroid cancer, thyroid hormone levels are iatrogenically varied,allowing the effect of high and low levels of thyroid hormone on Lp(a) to be determined.